Project 1 Abstract The goals of Project 1 are to define molecular events responsible for cause, severity, and treatment of ANCA glomerulonephritis (GN). Aim 1 will address the genetic basis for susceptibility to ANCA GN using results from a genome-wide associated study (GWAS) of North American patients with ANCA GN performed in collaboration with the Vasculitis Clinical Research Consortium and included over 550 samples from a UNC patient cohort. Associations found in this GWAS will be fine mapped to identify genetic variants within human leukocyte antigen (HLA) genes. Computational analysis of specific HLA variants can predict potential inciting autoantigen peptides. These peptides will used to identify autoreactive T cells and characterize the response of these T cells. The results of this aim will inform what causes the disease in some people and may provide a potential therapy by tolerizing patients to the inciting autoantigen. Aim 2 and 3 we will dissect molecular events that distinguish active disease from remission. Aim 2 is based on studies implicating expression of the autoantigen correlates with disease activity and the expression differences between patients with active or remitting disease are regulated by epigenetic changes. The distribution and levels of histone modifications and DNA methylation will reveal an epigenetic signature that distinguishes active disease from remission. These results will provide a rationale for using therapies targeted against epigenetic regulation. Aim 3 will survey the transcriptional landscape of total leukocytes and 4 different cell types (neutrophils, monocytes, T cells, and myeloid derived suppressor-like cells) important in ANCA GN. Gene expression results will be used to establish a transcriptional signature that distinguishes active disease from remission. A panel of a subset of genes within this signature can be used to monitor disease status, which could ultimately guide clinicians in their choice of therapy. Expression data will be interrogated with genotypes from GWAS to map expression quantitative trait loci associated with disease activity. Finally, Aim 3 will directly tackle the issue of therapy by comparing the transcriptional profiles from patients with ANCA GN to the Connectivity Map, which is a compilation of transcriptional changes among cells lines following treatment with FDA approved drugs. This comparison will identify drugs that agonize or antagonize the transcriptional signature in ANCA GN, and importantly, is the rationale for repurposing drugs to treat ANCA GN. Project 1 addresses the primary questions of patients with ANCA GN: What caused the disease? What makes it more or less severe? How can it be treated?